Tamoxifen is well known for its actions as an antagonist of estrogen receptor-mediated signaling and is one of the most extensively used endocrine agents both in the clinic and in the research setting. Tamoxifen has emerged from recent Breast Cancer Prevention Trials, conducted to evaluate risk reduction, as an effective preventive agent. Specifically, comparing tamoxifen to placebo (for 5 years) has shown that tamoxifen: (a) significantly reduced the risk of breast cancer recurrence, in those with a history of the disease; (b) reduced or delayed breast cancer progression, from an noninvasive to invasive breast cancer; (c) prevented or substantially reduced the risk of getting breast cancer (risk of occurrence) in healthy women with risk factors. The extraordinary outcomes offer support for the use of tamoxifen in multilevel preventive approaches and predict that it will continue to be vital in facilitating mechanistic studies. Information produced by mechanistic studies is needed to understand how to prevent cancer and how to confront treatment problems such as resistance. Molecular determinants of the resistant phenotype to tamoxifen are currently being identified. The next major effort will be to link these determinants to readily detectable biological changes that could be used to indicate the development of resistance before clinical manifestations develop.